Low prevalence of known pathogenic mutations in dominant PD genes: A Swedish multicenter study

Abstract

To determine the frequency of mutations known to cause autosomal dominant Parkinson disease (PD) in a series with more than 10% of Sweden's estimated number of PD patients. Methods: The Swedish Parkinson Disease Genetics Network was formed as a national multicenter consortium of clinical researchers who together have access to DNA from a total of 2,206 PD patients; 85.4% were from population-based studies. Samples were analyzed centrally for known pathogenic mutations in SNCA (duplications/triplications, p.Ala30Pro, p.Ala53Thr) and LRRK2 (p.Asn1437His, p.Arg1441His, p.Tyr1699Cys, p.Gly2019Ser, p.Ile2020Thr). We compared the frequency of these mutations in Swedish patients with published PD series and the gnomAD database. Results: A family history of PD in first-and/or second-degree relatives was reported by 21.6% of participants. Twelve patients (0.54%) carried LRRK2 p.(Gly2019Ser) mutations, one patient (0.045%) an SNCA duplication. The frequency of LRRK2 p.(Gly2019Ser) carriers was 0.11% in a matched Swedish control cohort and a similar 0.098% in total gnomAD, but there was a marked difference between ethnicities in gnomAD, with 42-fold higher frequency among Ashkenazi Jews than all others combined. Conclusions: In relative terms, the LRRK2 p.(Gly2019Ser) variant is the most frequent mutation among Swedish or international PD patients, and in gnomAD. SNCA duplications were the second most common of the mutations examined. In absolute terms, however, these known pathogenic variants in dominant PD genes are generally very rare and can only explain a minute fraction of familial aggregation of PD. Additional genetic and environmental mechanisms may explain the frequent co-occurrence of PD in close relatives.

Replication‐Based Rearrangements Are a Common Mechanism for SNCA Duplication in Parkinson's Disease

“…However, whole‐gene multiplications had been more frequently detected than the single‐nucleotide variants (SNVs). It has been reported that multiplications of SNCA are observed in around 0.05% of European PD patient populations . Other genes related to hereditary forms of PD have copy number variations (CNVs) demonstrating the role of loss of function .…”

Insights on Genetic and Environmental Factors in Parkinson’s Disease from a Regional Swedish Case-Control Cohort

“…This variant was genotyped in our dataset but excluded during the pre-imputation QC due to low MAF (0.2%). Previous studies of PD cohorts in Sweden have shown that the prevalence of LRRK2 G2019S carriers is low in Sweden, 0.54% of screened 2206 PD patients were carriers [ 71 ]. It has been estimated that the G2019S mutation worldwide accounts for 4% of familial and 1% of idiopathic PD cases [ 72 ].…”

Insights on Genetic and Environmental Factors in Parkinson’s Disease from a regional Swedish Case-Control Cohort

“…The individuals that had been inaccurate imputed for the LRRK2 G2019S did not have a noticeable effect on the overall GRS in the cohort. Previous studies of PD cohorts in Sweden have shown that the prevalence of LRRK2 G2019S carriers is low in Sweden, 0.54% of screened 2206 PD patients were carriers (72). It has been estimated that the G2019S mutation accounts for 4% of familial and 1% of idiopathic PD cases (73).…”

“…This variant was genotyped in our dataset but excluded during the pre-imputation QC due to low MAF (0.2%). Previous studies of PD cohorts in Sweden have shown that the prevalence of LRRK2 G2019S carriers is low in Sweden, 0.54% of screened 2206 PD patients were carriers [72]. It has been estimated that the G2019S mutation worldwide accounts for 4% of familial and 1% of idiopathic PD cases [73].…”